Cephalosporin antibiotics are widely used for the remedy of diseases caused by pathogenic bacteria, and these are said to be effective for the remedy of diseases caused by such bacteria as tolerant to any other antibiotics such as penicillin-type antibiotics. Regarding the remedial effect of these antibiotics in clinical use, however, the effect can hardly be said sufficient even in the case of so-called cephem-type antibiotics of the third generation which have recently been developed as antibiotics against gram-negative bacteria including opportunistic pathogens.
For instance, cephalosporin derivatives in which the 2-amino group in the 7-aminothiazolylglycyl group is amidated with dihdroxybenzoic acid to form an amido-substituted compound are noted to have a strong bactericidal activity against Pseudomonas aeruginosa (refer to Japanese patent application OPI No. 139387/84; the term "OPI" as used herein means an "unexamined published application"), but these are defective as being easily O-methylated and deactivated in a living body.
Japanese patent application OPI No. 118792/84 discloses one example of cephalosporin antibiotics, in which the 2-amino group in the 7-aminothiazolylglycyl group is amidated into 5-hydroxy-4-pyridone-2-carboxamide derivative. However, this essentially discloses carbacephem-type antibiotics, and any concrete examples of 1,5-dihydroxy-4-pyridone-2-carboxamide substituents of the present invention are not described at all in said patent publication.
The synthesis of the 1,5-dihydroxy-4-pyridone-2-carboxylic acid, which is one constitutional element in the 7-positioned substituent of the derivatives of the present invention, is not so easy. This is because N-aminopyridone compounds cannot almost be obtained by the reaction of a kojic acid and a hydrazine (refer to "Agr. Biol. Chem", Vol. 31, pp. 979-989, written by I. Ichimoto, et al. in 1967); and thus, when a pyrone ring is reacted with a hydroxyl-amine, not only the hydroxylamine-substitution on the intended oxygen atom but also the hydroxylamine-substitution on the carbonyl group is generally observed (refer to "Heterocyclic Compounds, Pyridine and its Derivatives", Vol. 14, Part 2, published by Interscience Publishers Ltd.).
Under the circumstances, the present inventors have earnestly studied various relevant techniques and have found that the said compound may be obtained in a relatively high yield by carrying out the reaction in the presence of pyridine or the like compound.
The compounds of the present invention are characterized by the existence of the 1,5-dihydroxy-4-pyridone-2-carboxamido group in the 7-positioned substituent therein; and the present compounds have an unexpectedly intensified and higher bacterial activity against various bacteria, especially against Pseudomonas aeruginosa, than the known 5-hydroxy-4-pyridone-2-carboxamido-substituted derivatives, and further, the present compounds have higher solubility in water, which is an important matter for injections. The present invention provides the new cephalosporin derivatives and concretely illustrates hereinafter the preparation and the use of these derivatives.